Clinical Effects of Recently Developed Antipsychotic Drugs in Schizophrenia

Schizophrenia and schizoaffective disorder are generally treated with second- generation antipsychotic drugs. These drugs are mostly dopaminergic (D2) and serotonergic (5-HT2A) antagonists. They sufficiently improve positive schizophrenia symptoms; however, they ameliorate negative symptoms and cognitive functions only to a limited extent.

We review novel antipsychotic drugs that exert partial agonism at dopaminergic and serotonergic receptors, such as cariprazine, brexpiprazole, and lumateperone. In addition, the mechanisms of action of non-dopaminergic antipsychotic drugs are described. Updated neural network models are used to explain the mechanisms of action of muscarinic (M4 and M1) receptor agonists (e.g., xanomeline combined with trospium) and trace-amine-associated receptor 1 (TAAR1) agonists (e.g., ulotaront). Phase 3 clinical trials of new third-generation antipsychotic drugs are also presented.

Novel antipsychotic drugs with partial agonism at D2 and D3 receptors improve positive and negative schizophrenia symptoms, as well as cognitive symptoms, more effectively than second- generation antipsychotic drugs. They are also well tolerated. M4 and M1 receptor agonists (i.e., xanomeline combined with trospium or emraclidine) and TAAR1 agonists (i.e., ulotaront) substantially improve negative schizophrenia symptoms and cognitive functions. These new nondopaminergic antipsychotic drugs better ameliorate negative symptoms and improve cognitive functions compared with second-generation antipsychotic drugs.

Results from phase 3 clinical studies indicate the clinical efficacy of new thirdgeneration antipsychotic drugs.

Promising new antipsychotic drugs include cariprazine, brexpiprazole, lumateperone, ulotaront, and xanomeline combined with trospium. Phase 3 clinical studies have shown therapeutic effects superior to those achieved with second-generation antipsychotic drugs.